title: Reduced effectiveness of CD4+Foxp3+ regulatory T cells in CD28-deficient NOD.H-2h4 mice leads to increased severity of spontaneous autoimmune thyroiditis.
abstract: NOD.H-2h4 mice given NaI in their drinking water develop iodine-accelerated spontaneous autoimmune thyroiditis (ISAT) with chronic inflammation of the thyroid by T and B cells and production of anti-mouse thyroglobulin (MTg) autoantibody. CD28(-/-) NOD.H-2h4 mice, which have reduced numbers of CD4(+)Foxp3(+) regulatory T cells (Tregs), were developed to examine the role of Tregs in ISAT development. CD28(-/-) NOD.H2-h4 mice develop more severe ISAT than do wild-type (WT) mice, with collagen deposition (fibrosis) and low serum T4. CD28(-/-) mice have increased expression of proinflammatory cytokines IFN-γ and IL-6, consistent with increased mononuclear cell infiltration and tissue destruction in thyroids. Importantly, transferring purified CD4(+)Foxp3(+) Tregs from WT mice reduces ISAT severity in CD28(-/-) mice without increasing the total number of Tregs, suggesting that endogenous Tregs in CD28(-/-) mice are functionally ineffective. Endogenous CD28(-/-) Tregs have reduced surface expression of CD27, TNFR2 p75, and glucocorticoid-induced TNFR-related protein compared with transferred CD28(+/+) Tregs. Although anti-MTg autoantibody levels generally correlate with ISAT severity scores in WT mice, CD28(-/-) mice have lower anti-MTg autoantibody responses than do WT mice. The percentages of follicular B cells are decreased and those of marginal zone B cells are increased in spleens of CD28(-/-) mice, and they have fewer thyroid-infiltrating B cells than do WT mice. This suggests that CD28 deficiency has direct and indirect effects on the B cell compartment. B cell-deficient (B(-/-)) NOD.H-2h4 mice are resistant to ISAT, but CD28(-/-)B(-/-) mice develop ISAT comparable to WT mice and have reduced numbers of Tregs compared with WT B(-/-) mice.
authors.affiliation: Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212;
authors.forename: Jason S
authors.initials: JS
authors.lastname: Ellis
authors.forename: So-Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Habib
authors.initials: H
authors.lastname: Zaghouani
authors.forename: Helen
authors.initials: H
authors.lastname: Braley-Mullen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D018106:CD28 Antigens / Q000172:deficiency*; D015704:CD4 Antigens / Q000378:metabolism; D005355:Fibrosis / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D018655:Lymphocyte Count; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012974:Sodium Iodide / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013954:Thyroglobulin / Q000276:immunology; D013961:Thyroid Gland / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000139:chemically induced / Q000276:immunology*; D013974:Thyroxine / Q000097:blood; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D018106:CD28 Antigens; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D047889:Receptors, Tumor Necrosis Factor, Type II; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D007371:Interferon-gamma; D013954:Thyroglobulin; D012974:Sodium Iodide; D013974:Thyroxine